Renal Nerve Stimulation Method for Treatment of Patients

ABSTRACT

A method and apparatus for treatment of heart failure, hypertension and renal failure by stimulating the renal nerve. The goal of therapy is to reduce sympathetic activity of the renal nerve. Therapy is accomplished by at least partially blocking the nerve with drug infusion or electrostimulation. Apparatus can be permanently implanted or catheter based.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/361,019 filed Jan. 30, 2012, which is a continuation of U.S.application Ser. No. 11/688,178 filed Mar. 19, 2007, now U.S. Pat. No.8,131,372, which is a continuation of U.S. application Ser. No.11/144,173 filed Jun. 3, 2005, now U.S. Pat. No. 7,647,115, which is acontinuation of U.S. application Ser. No. 10/408,665 filed Apr. 8, 2003,now U.S. Pat. No. 7,162,303 which claims benefit of U.S. ProvisionalAppl. No. 60/370,190 filed Apr. 8, 2002, and claims benefit of U.S.Provisional Appl. No. 60/415,575 filed Oct. 3, 2002, and claims benefitof U.S. Provisional Appl. No. 60/442,970 filed Jan. 29, 2003.

FIELD OF THE INVENTION

This invention relates to methods and apparatus for treatment ofcongestive heart failure, chronic renal failure and hypertension bynerve stimulation. In particular, the invention relates to theimprovement of these conditions of patients by blocking signals to therenal (kidney) nerve.

BACKGROUND OF THE INVENTION

The Heart Failure Problem:

Congestive Heart Failure (CHF) is a form of heart disease stillincreasing in frequency. According to the American Heart Association,CHF is the “Disease of the Next Millennium”. The number of patients withCHF is expected to grow even more significantly as an increasing numberof the “Baby Boomers” reach 50 years of age. CHF is a condition thatoccurs when the heart becomes damaged and reduces blood flow to theorgans of the body. If blood flow decreases sufficiently, kidneyfunction becomes impaired and results in fluid retention, abnormalhormone secretions and increased constriction of blood vessels. Theseresults increase the workload of the heart and further decrease thecapacity of the heart to pump blood through the kidney and circulatorysystem. This reduced capacity further reduces blood flow to the kidney,which in turn further reduces the capacity of the blood. It is believedthat the progressively-decreasing perfusion of the kidney is theprincipal non-cardiac cause perpetuating the downward spiral of the“Vicious Cycle of CHF”. Moreover, the fluid overload and associatedclinical symptoms resulting from these physiologic changes arepredominant causes for excessive hospital admissions, terrible qualityof life and overwhelming costs to the health care system due to CHF.

While many different diseases may initially damage the heart, oncepresent, CHF is split into two types: Chronic CHF and Acute (orDecompensated-Chronic) CHF. Chronic Congestive Heart Failure is a longerterm, slowly progressive, degenerative disease. Over years, chroniccongestive heart failure leads to cardiac insufficiency. Chronic CHF isclinically categorized by the patient's ability to exercise or performnormal activities of daily living (such as defined by the New York HeartAssociation Functional Class). Chronic CHF patients are usually managedon an outpatient basis, typically with drugs.

Chronic CHF patients may experience an abrupt, severe deterioration inheart function, termed Acute Congestive Heart Failure, resulting in theinability of the heart to maintain sufficient blood flow and pressure tokeep vital organs of the body alive. These acute CHF deteriorations canoccur when extra stress (such as an infection or excessive fluidoverload) significantly increases the workload on the heart in a stablechronic CHF patient. In contrast to the stepwise downward progression ofchronic CHF, a patient suffering acute CHF may deteriorate from even theearliest stages of CHF to severe hemodynamic collapse. In addition,Acute CHF can occur within hours or days following an Acute MyocardialInfarction (AMI), which is a sudden, irreversible injury to the heartmuscle, commonly referred to as a heart attack.

Normal Kidney Function:

The kidneys are a pair of organs that lie in the back of the abdomen oneach side of the vertebral column. Kidneys play an important regulatoryrole in maintaining the homeostatic balance of the body. The kidneysfunction like a complex chemical plant. The kidneys eliminate foreignchemicals from the body, regulate inorganic substances and theextracellular fluid, and function as endocrine glands, secretinghormonal substances like renin and erythropoietin.

The main functions of the kidney are to maintain the water balance ofthe body and control metabolic homeostasis. Healthy kidneys regulate theamount of fluid in the body by making the urine more or lessconcentrated, thus either reabsorbing or excreting more fluid,respectively. In case of renal disease, some normal and importantphysiological functions become detrimental to the patient's health. Thisprocess is called overcompensation. In the case of Chronic Renal Failure(CRF) patients overcompensation often manifests in hypertension(pathologically high blood pressure) that is damaging to heart and bloodvessels and can result in a stroke or death.

The functions of the kidney can be summarized under three broadcategories: a) filtering blood and excreting waste products generated bythe body's metabolism; b) regulating salt, water, electrolyte andacid-base balance; and c) secreting hormones to maintain vital organblood flow. Without properly functioning kidneys, a patient will sufferwater retention, reduced urine flow and an accumulation of wastes toxinsin the blood and body.

The primary functional unit of the kidneys that is involved in urineformation is called the “nephron”. Each kidney consists of about onemillion nephrons. The nephron is made up of a glomerulus and itstubules, which can be separated into a number of sections: the proximaltubule, the medullary loop (loop of Henle), and the distal tubule. Eachnephron is surrounded by different types of cells that have the abilityto secrete several substances and hormones (such as renin anderythropoietin). Urine is formed as a result of a complex processstarting with the filtration of plasma water from blood into theglomerulus. The walls of the glomerulus are freely permeable to waterand small molecules but almost impermeable to proteins and largemolecules. Thus, in a healthy kidney, the filtrate is virtually free ofprotein and has no cellular elements. The filtered fluid that eventuallybecomes urine flows through the tubules. The final chemical compositionof the urine is determined by the secretion into and reabsorbtion ofsubstances from the urine required to maintain homeostasis.

Receiving about 20% of cardiac output, the two kidneys filter about 125ml of plasma water per minute. This is called the Glomerular FiltrationRate (GFR) and is the gold standard measurement of the kidney function.Since measurement of GFR is very cumbersome and expensive, clinically,the serum creatinine level or creatinine clearance are used assurrogates to measure kidney function. Filtration occurs because of apressure gradient across the glomerular membrane. The pressure in thearteries of the kidney pushes plasma water into the glomerulus causingfiltration. To keep the GFR relatively constant, pressure in theglomerulus is held constant by the constriction or dilatation of theafferent and efferent arterioles, the muscular walled vessels leading toand from each glomerulus.

Abnormal Kidney Function in CHF:

The kidneys maintain the water balance of the body and control metabolichomeostasis. The kidneys regulate the amount of fluid in the body bymaking the urine more or less concentrated, thus either reabsorbing orexcreting more fluid, respectively. Without properly functioningkidneys, a patient will suffer water retention, reduced urine flow andan accumulation of wastes toxins in the blood and body. These conditionsresulting from reduced renal function or renal failure (kidney failure)are believed to increase the workload of the heart. In a CHF patient,renal failure will cause the heart to further deteriorate as the waterbuild-up and blood toxins accumulate due to the poorly functioningkidneys and in turn, cause the heart further harm.

In a CHF patient, for any of the known cause of heart dysfunction, theheart will progressively fail and blood flow and pressure will drop inthe patients circulatory system. In the acute heart failure, theshort-term compensations serve to maintain perfusion to critical organs,notably the brain and the heart that cannot survive prolonged reductionin blood flow. In chronic heart failure, these same responses thatinitially aided survival in acute heart failure can become deleterious.

A combination of complex mechanisms contribute to the deleterious fluidoverload in CHF. As the heart fails and blood pressure drops, thekidneys cannot function owing to insufficient blood pressure forperfusion and become impaired. This impairment in renal functionultimately leads to a decrease in urine output. Without sufficient urineoutput, the body retains fluids and the resulting fluid overload causesperipheral edema (swelling of the legs), shortness of breath (from fluidin the lungs), and fluid in the abdomen, among other undesirableconditions in the patient.

In addition, the decrease in cardiac output leads to reduced renal bloodflow, increased neurohormonal stimulus, and release of the hormone reninfrom the juxtaglomerular apparatus of the kidney. This results in avidretention of sodium and thus volume expansion. Increased rennin resultsin the formation of angiotensin, a potent vasoconstrictor.

Heart failure and the resulting reduction in blood pressure reduces theblood flow and perfusion pressure through organs in the body, other thanthe kidneys. As they suffer reduced blood pressure, these organs maybecome hypoxic causing the development of a metabolic acidosis whichreduces the effectiveness of pharmacological therapy as well asincreases the risk of sudden death.

This spiral of deterioration that physicians observe in heart failurepatients is believed to be mediated, in large part, by activation of asubtle interaction between heart function and kidney function, known asthe renin-angiotensin system. Disturbances in the heart's pumpingfunction results in decreased cardiac output and diminished blood flow.The kidneys respond to the diminished blood flow as though the totalblood volume was decreased, when in fact the measured volume is normalor even increased. This leads to fluid retention by the kidneys andformation of edema causing fluid overload and increased stress on theheart.

Systemically, CHF is associated with an abnormally elevated peripheralvascular resistance and is dominated by alterations of the circulationresulting from an intense disturbance of sympathetic nervous systemfunction. Increased activity of the sympathetic nervous system promotesa downward vicious cycle of increased arterial vasoconstriction(increased resistance of vessels to blood flow) followed by a furtherreduction of cardiac output, causing even more diminished blood flow tothe vital organs.

In CHF via the previously explained mechanism of vasoconstriction, theheart and circulatory system dramatically reduces blood flow to kidneys.During CHF, the kidneys receive a command from higher neural centers vianeural pathways and hormonal messengers to retain fluid and sodium inthe body. In response, to stress on the heart, the neural centerscommand the kidneys to reduce their filtering functions. While in theshort term, these commands can be beneficial, if these commands continueover hours and days they can jeopardize the person's life or make theperson dependent on artificial kidney for life by causing the kidneys tocease functioning.

When the kidneys do not fully filter the blood, a huge amount of fluidis retained in the body resulting in bloating (fluid in tissues), andincreases the workload of the heart. Fluid can penetrate into the lungsand the patient becomes short of breath. This odd and self-destructivephenomenon is most likely explained by the effects of normalcompensatory mechanisms of the body that improperly perceive thechronically low blood pressure of CHF as a sign of temporary disturbancesuch as bleeding.

In an acute situation, the organism tries to protect its most vitalorgans, the brain and the heart, from the hazards of oxygen deprivation.Commands are issued via neural and hormonal pathways and messengers.These commands are directed toward the goal of maintaining bloodpressure to the brain and heart, which are treated by the body as themost vital organs. The brain and heart cannot sustain low perfusion forany substantial period of time. A stroke or a cardiac arrest will resultif the blood pressure to these organs is reduced to unacceptable levels.Other organs, such as kidneys, can withstand somewhat longer periods ofischemia without suffering long-term damage. Accordingly, the bodysacrifices blood supply to these other organs in favor of the brain andthe heart.

The hemodynamic impairment resulting from CHF activates severalneurohormonal systems, such as the renin-angiotensin and aldosteronesystem, sympatho-adrenal system and vasopressin release. As the kidneyssuffer from increased renal vasoconstriction, the filtering rate (GFR)of the blood drops and the sodium load in the circulatory systemincreases. Simultaneously, more renin is liberated from thejuxtaglomerular of the kidney. The combined effects of reduced kidneyfunctioning include reduced glomerular sodium load, analdosterone-mediated increase in tubular reabsorption of sodium, andretention in the body of sodium and water. These effects lead to severalsigns and symptoms of the CHF condition, including an enlarged heart,increased systolic wall stress, an increased myocardial oxygen demand,and the formation of edema on the basis of fluid and sodium retention inthe kidney. Accordingly, sustained reduction in renal blood flow andvasoconstriction is directly responsible for causing the fluid retentionassociated with CHF.

In view of the physiologic mechanisms described above it is positivelyestablished that the abnormal activity of the kidney is a principalnon-cardiac cause of a progressive condition in a patient suffering fromCHF.

Growing population of late stage CHF patients is an increasing concernfor the society. The disease is progressive, and as of now, not curable.The limitations of drug therapy and its inability to reverse or evenarrest the deterioration of CHF patients are clear. Surgical therapiesare effective in some cases, but limited to the end-stage patientpopulation because of the associated risk and cost. There is clearly aneed for a new treatment that will overcome limitations of drug therapybut will be less invasive and costly than heart transplantation.

Similar condition existed several decades ago in the area of cardiacarrhythmias. Limitations of anti-arrhythmic drugs were overcome by theinvention of heart pacemakers. Widespread use of implantable electricpacemakers resulted in prolonged productive life for millions of cardiacpatients. So far, all medical devices proposed for the treatment of CHFare cardio-centric i.e., focus on the improvement of the heart function.The dramatic role played by kidneys in the deterioration of CHF patientshas been overlooked by the medical device industry.

Neural Control of Kidneys:

The autonomic nervous system is recognized as an important pathway forcontrol signals that are responsible for the regulation of bodyfunctions critical for maintaining vascular fluid balance and bloodpressure. The autonomic nervous system conducts information in the formof signals from the body's biologic sensors such as baroreceptors(responding to pressure and volume of blood) and chemoreceptors(responding to chemical composition of blood) to the central nervoussystem via its sensory fibers. It also conducts command signals from thecentral nervous system that control the various innervated components ofthe vascular system via its motor fibers.

Experience with human kidney transplantation provided early evidence ofthe role of the nervous system in the kidney function. It was noted thatafter the transplant, when all the kidney nerves are totally severed,the kidney increased the excretion of water and sodium. This phenomenonwas also observed in animals when the renal nerves were cut orchemically destroyed. The phenomenon was called “denervation diuresis”since the denervation acted on a kidney similar to a diureticmedication. Later the “denervation diuresis” was found to be associatedwith the vasodilatation the renal arterial system that led to theincrease of the blood flow through the kidney. This observation wasconfirmed by the observation in animals that reducing blood pressuresupplying the kidney could reverse the “denervation diuresis”.

It was also observed that after several months passed after thetransplant surgery in successful cases, the “denervation diuresis” intransplant recipients stopped and the kidney function returned tonormal. Originally it was believed that the “renal diuresis” is atransient phenomenon and that the nerves conducting signals from thecentral nervous system to the kidney are not essential for the kidneyfunction. Later, new discoveries led to the different explanation. It isbelieved now that the renal nerves have a profound ability to regenerateand the reversal of the “denervation diuresis” shall be attributed tothe growth of the new nerve fibers supplying kidneys with the necessarystimuli.

Another body of research that is of particular importance for thisapplication was conducted in the period of 1964-1969 and focused on therole of the neural control of secretion of the hormone renin by thekidney. As was discussed previously, renin is a hormone responsible forthe “vicious cycle” of vasoconstriction and water and sodium retentionin heart failure patients. It was demonstrated that increase (renalnerve stimulation) or decrease (renal nerve denervation) in renalsympathetic nerve activity produced parallel increases and decreases inthe renin secretion rate by the kidney, respectively.

In summary, it is known from clinical experience and the large body ofanimal research that the stimulation of the renal nerve leads to thevasoconstriction of blood vessels supplying the kidney, decreased renalblood flow, decreased removal of water and sodium from the body andincreased renin secretion. These observations closely resemble thephysiologic landscape of the deleterious effects of the chroniccongestive heart failure. It is also known that the reduction of thesympathetic renal nerve activity, achieved by denervation, can reversethese processes.

It was established in animal models that the heart failure conditionresults in the abnormally high sympathetic stimulation of the kidney.This phenomenon was traced back to the sensory nerves conducting signalsfrom baroreceptors to the central nervous system. Baroreceptors are thebiologic sensors sensitive to blood pressure. They are present in thedifferent locations of the vascular system. Powerful relationship existsbetween the baroreceptors in the carotid arteries (supplying brain witharterial blood) and the sympathetic nervous stimulus to the kidneys.When the arterial blood pressure was suddenly reduced in experimentalanimals with heart failure, the sympathetic tone increased. Neverthelessthe normal baroreflex alone, cannot be responsible for the elevatedrenal nerve activity in chronic CHF patients. If exposed to the reducedlevel of arterial pressure for a prolonged time baroreceptors normally“reset” i.e. return to the baseline level of activity until a newdisturbance is introduced. Therefore, in chronic CHF patients thecomponents of the autonomic nervous system responsible for the controlof blood pressure and the neural control of the kidney function becomeabnormal. The exact mechanisms that cause this abnormality are not fullyunderstood but, its effects on the overall condition of the CHF patientsare profoundly negative.

End Stage Renal Disease Problem:

There is a dramatic increase in patients with end-stage renal disease(ESRD) due to diabetic nephropathy, chronic glomerulonephritis anduncontrolled hypertension. In the US alone, 372,000 patients requireddialysis in the year 2000. There were 90,000 new cases of ESRD in 1999with the number of patients on dialysis is expected to rise to 650,000by the year 2010. The trends in Europe and Japan are forecasted tofollow a similar path. Mortality in patients with ESRD remains 10-20times higher than that in the general population. Annual Medicarepatient costs $52,868 for dialysis and $18,496 for transplantation. Thetotal cost for Medicare patients with ESRD in 1998 was $12.04 billion.

The primary cause of these problems is the slow relentless progressionof Chronic Renal Failure (CRF) to ESRD. CRF represents a critical periodin the evolution of ESRD. The signs and symptoms of CRF are initiallyminor, but over the course of 2-5 years, become progressive andirreversible. Until the 1980's, there were no therapies that couldsignificantly slow the progression of CRF to ESRD. While some progresshas been made in combating the progression to and complications of ESRDin last two decades, the clinical benefits of existing interventionsremain limited with no new drug or device therapies on the horizon.

Progression of Chronic Renal Failure:

It has been known for several decades that renal diseases of diverseetiology (hypotension, infection, trauma, autoimmune disease, etc.) canlead to the syndrome of CRF characterized by systemic hypertension,proteinuria (excess protein filtered from the blood into the urine) anda progressive decline in GFR ultimately resulting in ESRD. Theseobservations suggested that CRF progresses via a common pathway ofmechanisms, and that therapeutic interventions inhibiting this commonpathway may be successful in slowing the rate of progression of CRFirrespective of the initiating cause.

To start the vicious cycle of CRF, an initial insult to the kidneycauses loss of some nephrons. To maintain normal GFR, there is anactivation of compensatory renal and systemic mechanisms resulting in astate of hyperfiltration in the remaining nephrons. Eventually, however,the increasing numbers of nephrons “overworked” and damaged byhyperfiltration are lost. At some point, a sufficient number of nephronsare lost so that normal GFR can no longer be maintained. Thesepathologic changes of CRF produce worsening systemic hypertension, thushigh glomerular pressure and increased hyperfiltration. Increasedglomerular hyperfiltration and permeability in CRF pushes an increasedamount of protein from the blood, across the glomerulus and into therenal tubules. This protein is directly toxic to the tubules and leadsto further loss of nephrons, increasing the rate of progression of CRF.This vicious cycle of CRF continues as the GFR drops, with loss ofadditional nephrons leading to further hyperfiltration and eventually toESRD requiring dialysis. Clinically, hypertension and excess proteinfiltration have been shown to be two major determining factors in therate of progression of CRF to ESRD.

Though previously clinically known, it was not until the 1980s that thephysiologic link between hypertension, proteinuria, nephron loss and CRFwas identified. In 1990s the role of sympathetic nervous system activitywas elucidated. Afferent signals arising from the damaged kidneys due tothe activation of mechanoreceptors and chemoreceptors stimulate areas ofthe brain responsible for blood pressure control. In response brainincreases sympathetic stimulation on the systemic level resulting in theincreased blood pressure primarily through vasoconstriction of bloodvessels.

When elevated sympathetic stimulation reaches the kidney via theefferent sympathetic nerve fibers, it produces major deleterious effectsin two forms:

A. Kidney is damaged by direct renal toxicity from the release ofsympathetic neurotransmitters (such as norepinephrine) in the kidneyindependent of the hypertension.

B. Secretion of renin that activates Angiotensin II is increased leadingto the increased systemic vasoconstriction and exacerbated hypertension.

Over time damage to the kidney leads to further increase of afferentsympathetic signals from the kidney to the brain. Elevated AngiotensinII further facilitates internal renal release of neurotransmitters. Thefeedback loop is therefore closed accelerating the deterioration of thekidney.

BRIEF DESCRIPTION OF THE INVENTION

A treatment of heart failure, renal failure and hypertension has beendeveloped to arrest or slow down the progression of the disease. Thistreatment is expected to delay the morbid conditions and death oftensuffered by CHF patients and to delay the need for dialysis in renalfailure. This treatment is expected to control hypertension in patientsthat do not respond to drugs or require multiple drugs.

The treatment includes a device and method that reduces the abnormallyelevated sympathetic nerve signals that contribute to the progression ofheart and renal disease. The desired treatment should be implementedwhile preserving a patient's mobility and quality of life without therisk of major surgery.

The treatment breaks with tradition and proposes a counterintuitivenovel method and apparatus of treating heart failure, renal failure andhypertension by electrically or chemically modulating the nerves of thekidney. Elevated nerve signals to and from the kidney are a commonpathway of the progression of these chronic conditions.

Chronic heart and renal failure is treated by reducing the sympatheticefferent or afferent nerve activity of the kidney. Efferent nerves (asopposed to afferent) are the nerves leading from the central nervoussystem to the organ, in this case to the kidney. Sympathetic nervoussystem (as opposed to parasympathetic) is the part of the autonomicnervous system that is concerned especially with preparing the body toreact to situations of stress or emergency that tends to depresssecretion, decrease the tone and contractility of smooth muscle, andincrease heart rate. In the case of renal sympathetic activity, it ismanifested in the inhibition of the production of urine and excretion ofsodium. It also elevates the secretion of renin that triggersvasoconstriction. This mechanism is best illustrated by the response ofthe body to severe bleeding. When in experimental animals, the bloodpressure is artificially reduced by bleeding, and the sympatheticinhibition of the kidney is increased to maintain blood pressure with anultimate goal of preserving the brain from hypotension. The resultingvasoconstriction and fluid retention work in synchrony to help the bodyto maintain homeostasis.

Efferent renal nerve activity is considered postganglionic, autonomicand exclusively sympathetic. In general, efferent sympathetic nerves cancause a variety of responses in the innervated organs. Studies ofsympathetic renal nerves show that they have a strong tendency to behaveas a uniform population that acts as vasoconstrictors. The renalpostganglionic neurons are modulated by pregangleonic (ganglion is a“knot” or agglomeration of nerve sells) nerves that originate from thebrain and thoracic and upper lumbar regions of the spinal cord.

The pregangleonic nerves have diverse function and are likely to havehigh degree of redundancy. Although different pathways exist to achievereduced efferent renal nerve activity, the simplest way is to denervatethe postganglionic nerves with an electric stimulus or a chemical agent.The same desired affect could be achieved by total surgical, electric orchemical destruction (ablation) of the nerve. For two reasons this isnot a preferred pathway. As was described before, renal nervesregenerate and can grow back as soon as several months after surgery.Secondarily, total irreversible denervation of the kidney can result indanger to the patient. Overdiuresis or removal of excess water fromblood can result in the reduction of blood volume beyond the amount thatcan be rapidly replaced by fluid intake. This can result in hypovolemiaand hypotension. Hypotension is especially dangerous in heart failurepatients with the reduced capacity of the heart to pump blood andmaintain blood pressure. In addition, the vasodilation of the renalartery resulting from the renal denervation will cause a significantincrease in renal blood flow. In a healthy person, renal blood flow canamount to as much as 20% of the total cardiac output. In heart failurepatients cardiac output is reduced and the renal denervation can “steal”even larger fraction of it from circulation. This, in turn, can lead tohypotension. Also, in a heart failure patient the heart has limitedability to keep up with the demand for oxygenated blood that can becaused by even modest physical effort. Therefore a heart failure patientthat can sustain the increased blood flow to the kidneys while at restcan face serious complications resulting from acute hypotension, if thedemand for blood flow is increased by temperature change or exercise.

In view of the factors described above it is desired to have means toreduce the efferent sympathetic stimulation of the kidney in CHFpatients in a reversible, controlled fashion preferably based on aphysiologic feedback signal that is indicative of the oxygen demand bythe body, blood pressure, cardiac output of the patient or a combinationof these and other physiologic parameters.

The treatment also breaks with tradition and proposes a counterintuitivenovel method and apparatus of treating chronic renal failure (CRF) withthe goal of slowing down the progression of CRF to the ESRD byelectrically or chemically altering the sympathetic neural stimulationentering and exiting the kidney. The described method and apparatus canbe also used to treat hypertension in patients with renal disease orabnormal renal function.

To control the afferent nerve signals from the kidney to the brain andblock efferent nerve stimuli from entering the kidney (without systemicside effects of drug therapy), a renal nerve stimulator is implanted andattached to an electrode lead placed around or close to the renalartery. Stimulation effectively blocks or significantly reduces bothefferent and afferent signals traveling between the kidney, theautonomic nervous system and the central nervous system.

The benefits that may be possible by controlling renal nerve signals toreduce efferent overstimulation are:

a. The secretion of renin by kidney should be reduced by 40-50%translating into the proportionate reduction of systemic angiotensin II,resulting in the reduction of blood pressure in all hypertensivepatients including patients refractory to drugs.

b. Similar to renoprotective mechanisms of ACE-I, the reduction ofangiotensin II should result in slowed progression of intrarenal changesin glomerular structure and function independent of blood pressurecontrol.

c. Similar to the effects of moxonidine, reduced efferentoverstimulation should reduce damage by direct renal toxicity from therelease of sympathetic neurotransmitters.

Following the reduction of the afferent sympathetic renal feedback tothe brain, there is expected to be a marked reduction in the systemicefferent overstimulation. This will translate into the systemicvasodilation and reduction of hypertension independent of therenin-angiotensin II mechanism.

Renal nerve stimulation in hypertensive CRF patients is unlikely tocause clinically relevant episodes of hypotension. Systemic bloodpressure is tightly controlled by feedbacks from baroreceptors in aortaand carotid sinuses. These mechanisms are likely to take over if theblood pressure becomes too low. In polycystic kidney disease (PKD)patients who underwent surgery for total denervation of kidneys,denervation resolved hypertension without postoperative episodes ofhypotension.

Technique for Nerve Modulation

Nerve activity can be reversibly modulated in several different ways.Nerves can be stimulated with electric current or chemicals that enhanceor inhibit neurotransmission. In the case of electrical stimulation, astimulator containing a power source is typically connected to the nerveby wires or leads. Leads can terminate in electrodes, cuffs that enclosethe nerve or in conductive anchors (screws or hooks) that are embeddedin tissue. In the later case, the lead is designed to generatesufficient electric field to alter or induce current in the nervewithout physically contacting it. The electrodes or leads can by bipolaror unipolar. There are permanent leads that are implanted for months andyears to treat a chronic condition and temporary leads used to supportthe patient during an acute stage of the disease. The engineeringaspects of design and manufacturing of nerve stimulators, pacemakers,leads, anchors and nerve cuffs are well known.

Proposed clinical applications of nerve stimulation include: Depression,Anxiety, Alzheimer's Disease, Obesity, and others. In all existingclinical applications except pain control, the targeted nerves arestimulated to increase the intensity of the transmitted signal. Toachieve relief of hypertension and CRF signal traffic traveling to andfrom the kidney via renal nerves needs to be reduced. This can beachieved by known methods previously used in physiologic studies onanimals. A nerve can be paced with electric pulses at high rate or atvoltage that substantially exceed normal traffic. As a result, a nervewill be “overpaced”, run out of neurotransmitter substance and transmitless stimulus to the kidney. Alternatively relatively high voltagepotential can be applied to the nerve to create a blockade. This methodis known as “voltage clamping” of a nerve. Infusion of a small dose of alocal anesthetic in the vicinity of the nerve will produce the sameeffect.

Ablation of conductive tissue pathways is another commonly usedtechnique to control arterial or ventricular tachycardia of the heart.Ablation can be performed by introduction of a catheter into the venoussystem in close proximity of the sympathetic renal nerve subsequentablation of the tissue. Catheter based ablation devices were previouslyused to stop electric stimulation of nerves by heating nerve tissue withRF energy that can be delivered by a system of electrodes. RF energythus delivered stops the nerve conduction. U.S. Pat. No. 6,292,695describes in detail a method and apparatus for transvascular treatmentof tachycardia and fibrillation with nerve stimulation and ablation.Similar catheter based apparatus can be used to ablate the renal nervewith an intent to treat CRF. The method described in this invention isapplicable to irreversible ablation of the renal nerve by electricenergy, cold, or chemical agents such as phenol or alcohol.

Thermal means may be used to cool the renal nerve and adjacent tissue toreduce the sympathetic nerve stimulation of the kidney. Specifically,the renal nerve signals may be dampened by either directly cooling therenal nerve or the kidney, to reduce their sensitivity, metabolicactivity and function, or by cooling the surrounding tissue. An exampleof this approach is to use the cooling effect of the Peltier device.Specifically, the thermal transfer junction may be positioned adjacentthe vascular wall or a renal artery to provide a cooling effect. Thecooling effect may be used to dampen signals generated by the kidney.Another example of this approach is to use the fluid delivery device todeliver a cool or cold fluid (e.g. saline).

BRIEF DESCRIPTION OF THE DRAWINGS

A preferred embodiment and best mode of the invention is illustrated inthe attached drawings that are described as follows:

FIG. 1 illustrates the role of sympathetic renal nerve stimulation incongestive heart failure (CHF).

FIG. 2 illustrates the preferred implanted electrostimulation embodimentof the present invention.

FIG. 3 illustrates stimulation of renal nerves across the wall of therenal vein.

FIG. 4 illustrates the drug infusion blocking embodiment with animplanted drug pump.

FIG. 5 illustrates the arterial pressure based control algorithm forrenal nerve modulation.

FIG. 6 illustrates electrostimulation of the renal nerve with an anodalblock.

FIG. 7 illustrates different nerve fibers in a nerve bundle trunk.

FIG. 8 illustrates renal nerve modulation by blocking electric signalsat one point and stimulating the nerve at a different point.

FIG. 9 illustrates transvenous stimulation of the renal nerve withelectric field.

FIG. 10 illustrates an embodiment where the stimulation lead is placedusing laparoscopic surgery.

FIG. 11 illustrates a patient controlled stimulation embodiment.

FIG. 12 illustrates the progression of CRF to ESRD.

FIG. 13 illustrates the physiologic mechanisms of CRF.

FIG. 14 illustrates stimulation of renal nerves in a patient with animplanted stimulator with a renal artery cuff electrode.

FIG. 15 illustrates the placement of a stimulation cuff on a renalartery end nerve plexus.

FIG. 16 illustrates the design of the cuff electrode that wraps aroundan artery.

FIG. 17 illustrates the interface between cuff electrodes and the renalartery surface.

DETAILED DESCRIPTION OF THE INVENTION

A method and apparatus has been developed to regulate sympathetic nerveactivity to the kidney to improve a patient's renal function and overallcondition, and ultimately to arrest or reverse the vicious cycle of CHFdisease.

FIG. 1 illustrates the role of sympathetic renal nerves in heartfailure. Neural pathways are indicated by solid lines, hormones byinterrupted lines. Baroreceptors 101 respond to low blood pressureresulting from the reduced ability of the failing heart 103 to pumpblood. Unloading of baroreceptors 101 in the left ventricle of the heart103, carotid sinus, and aortic arch (not shown) generates afferentneural signals 113 that stimulate cardio-regulatory centers in the brain102. This stimulation results in activation of efferent pathways in thesympathetic nervous system 118. Sympathetic signals are transmitted tothe spinal cord 106, sympathetic ganglia 107 and via the sympatheticefferent renal nerve 109 to the kidney 111. The increased activity ofsympathetic nerves 108 also causes vasoconstriction 110 (increasedresistance) of peripheral blood vessels.

In the kidney 111 efferent sympathetic nerve stimulation 109 causesretention of water (reduction of the amount of urine) and retention ofsodium 112 an osmotic agent that is responsible for the expansion ofblood volume. The sympathetic stimulation of the kidney stimulates therelease of hormones renin 105 and angiotensin II. These hormonesactivate the complex renin-angiotensin-aldosterone system 117 leading tomore deleterious hormones causing vasoconstriction 104 and heart damage116. The sympathetic stimulation of the hypothalamus of the brain 102results in the release of the powerful hormone vasopressin 114 thatcauses further vasoconstriction of blood vessels. Angiotensin 11constricts blood vessels and stimulates the release of aldosterone fromadrenal gland (not shown). It also increases tubular sodium reabsorption(sodium retention) in the kidney 111 and causes remodeling of cardiacmyocytes therefore contributing to the further deterioration of theheart 103 and the kidney 111.

It can be inferred from the FIG. 1 that the renal efferent sympatheticstimulation in heart failure is caused by low blood pressure and is aprimary factor responsible for the most debilitating symptom of heartfailure i.e. fluid overload. It also contributes to the progression ofthe disease. Acting through the volume overload and peripheralvasoconstriction (together increasing load on the heart) it acceleratesthe enlargement of the left ventricle that in turn results in thedeteriorating ability of the heart to pump blood. Drugs used to treatheat failure address these issues separately. Diuretics are used toreduce fluid overload by reducing the reabsorption of sodium andincreasing the excretion of water 112. Vasodilators are used to reduceperipheral vasoconstriction 110 by reducing levels of angiotensin 117.Inotropic agents are used to increase blood pressure and de-activate thesignals from baroreceptors 101. These drugs have limited affect andultimately fail to control the progression and debilitating symptomsheart failure. The proposed invention corrects the neurohormonalmisbalance in heart failure by directly controlling the sympatheticneural stimulation 109 of the kidney 111.

FIG. 2 shows a patient 201 suffering from chronic congestive heartfailure treated in accordance with the invention. An implantable device202 is implanted in the patient's body. An implantable device can be anelectric device similar to a pacemaker or nerve stimulator or a chemicalsubstance infusion device. Such devices are well known in the field ofmedicine. Internal mechanism of the implantable device typicallyincludes a battery 203, an electronic circuit and (in the case of a drugdelivery device) a reservoir with medication.

An example of an implantable drug infusion device is the implantableinsulin pump system for treatment of diabetes sold as the MiniMed 2007or the SynchroMed Infusion System used to control chronic pain, bothmanufactured by Medtronic Inc. The drug used in this embodiment can be acommon local anesthetic such as Novocain or Lidocaine or a more longlasting equivalent anesthetic. Alternatively, a nerve toxin such as thebotox can be used to block the nerve. An example of an implantable nervestimulator is the Vagus Nerve Stimulation (VNS™) with the CyberonicsNeuroCybernetic Prosthesis (NCP®) System used for treatment of epilepsy.It is manufactured by Cyberonics Inc. The internal mechanism of theimplantable device typically includes a battery, an electronic circuitand (in the case of a drug delivery device), a reservoir withmedication. Neurostimulation systems from different manufacturers arevirtually identical across application areas, usually varying only inthe patterns of stimulating voltage pulses, style or number ofelectrodes used, and the programmed parameters. The basic implantablesystem consists of a pacemaker-like titanium case enclosing the powersource and microcircuitry that are used to create and regulate theelectrical impulses. An extension lead attached to this generatorcarries the electrical pulses to the electrode lead that is implanted orattached to the nerves or tissues to be stimulated.

The implantable device 202 is equipped with the lead 204 connecting itto the renal nerve 205. The lead can contain an electric wire system ora catheter for delivery of medication or both. Renal nerve conductsefferent sympathetic stimulation from the sympathetic trunk 206 to thekidney 208. Sympathetic trunk is connected to the patient's spinal cordinside the spine 207. The connection can be located between the kidney208 and the posterior renal or other renal ganglia (not shown) in theregion of the 10.sup.th, 11.sup.th and 12.sup.th thoracic and 1.sup.stlumbar segments of the spine 207.

The implantable device 202 is also equipped with the sensor lead 209terminated with the sensor 210. The sensor can be a pressure sensor oran oxygen saturation sensor. The sensor 210 can be located in the leftventricle of the heart 211, right atrium of the heart or other cavity ofthe heart. It can also be located outside of the heart in the aorta 213,the aortic arch 212 or a carotid artery 214. If the sensor is a pressuresensor, it is used to supply the device 202 with the informationnecessary to safely regulate the sympathetic nerve signals to the kidney208. A venous blood oxygen saturation signal can be used in a similarway to control the sympathetic nerve traffic based on oxygen demand. Thesensor will be placed in the right atrium of the heart or in the venacava. More than one sensor can be used in combination to supplyinformation to the device. Sensors can be inside the vascular system(blood vessels) or outside of it. For example, a motion sensor can beused to detect activity of the person. Such sensor does not requireplacement outside the implanted device case and can be integrated insidethe sealed case of the device 202 as a part of the internal mechanism.

FIG. 3 shows external renal nerve stimulator apparatus 306 connected tothe electrode tip 308 by the catheter 301. A catheter is inserted via aninsertion site 303 into the femoral vein 305 into the vena cava 302 andfurther into the renal vein 304. The tip 308 is then brought into theelectric contact with the wall of the vein 304. Hooks or screws, similarto ones used to secure pacemaker leads, can be used to anchor the tipand improve the electric contact. The tip 308 can have one, two or moreelectrodes integrated in its design. The purpose of the electrodes is togenerate the electric field sufficiently strong to influence trafficalong the renal nerve 205 stimulating the kidney 208.

Two potential uses for the embodiment shown on FIG. 3 are the acuteshort-term stimulation of the renal nerve and the implanted embodiment.For short term treatment, a catheter equipped with electrodes on the tipis positioned in the renal vein. The proximal end of the catheter isleft outside of the body and connected to the electro stimulationapparatus. For the implanted application, the catheter is used toposition a stimulation lead, which is anchored in the vessel and left inplace after the catheter is withdrawn. The lead is then connected to theimplantable stimulator that is left in the body and the surgical site isclosed. Patients have the benefit of mobility and lower risk ofinfection with the implanted stimulator-lead system.

Similar to the venous embodiment, an arterial system can be used.Catheter will be introduced via the femoral artery and aorta (not shown)into the renal artery 307. Arterial catheterization is more dangerousthan venous but may achieve superior result by placing stimulationelectrode (or electrodes) in close proximity to the renal nerve withoutsurgery.

FIG. 4 shows the use of a drug infusion pump 401 to block or partiallyblock stimulation of the kidney 208 by infiltrating tissue proximal tothe renal nerve 205 with a nerve-blocking drug. Pump 401 can be animplanted drug pump. The pump is equipped with a reservoir 403 and anaccess port (not shown) to refill the reservoir with the drug bypuncturing the skin of the patient and the port septum with an infusionneedle. The pump is connected to the infusion catheter 402 that issurgically implanted in the proximity of the renal nerve 205. The drugused in this embodiment can be a common local anesthetic such asNovocain. If it is desired to block the nerve for a long time after asingle bolus drug infusion, a nerve toxin such as botox (botulism toxin)can be used as a nerve-blocking drug. Other suitable nerve desensitizingagents may comprise, for example, tetrodotoxin or other inhibitor ofexcitable tissues.

FIG. 5 illustrates the use of arterial blood pressure monitoring tomodulate the treatment of CHF with renal nerve blocking. The bloodpressure is monitored by the computer controlled implanted device 202(FIG. 2) using the implanted sensor 210. Alternatively the controllingdevice can be incorporated in the external nerve stimulator 306 (FIG. 3)and connected to a standard blood pressure measurement device (notshown). The objective of control is to avoid hypotension that can becaused by excessive vasodilation of renal arteries caused by suppressionof renal sympathetic stimulus. This may cause the increase of renalblood flow dangerous for the heart failure patient with the limitedheart pumping ability. The control algorithm increases or decreases thelevel of therapy with the goal of maintaining the blood pressure withinthe safe range. Similarly the oxygen content of venous or arterial bloodcan be measured and used to control therapy. Reduction of blood oxygenis an indicator of insufficient cardiac output in heart failurepatients.

FIG. 6 illustrates the principles of modulating renal nerve signal withan anodal block. Renal nerve 601 conducts efferent sympathetic electricsignals in the direction towards the kidney 602. Renal nerve 601 trunkis enveloped with two conductive cuff type electrodes: the anode 603 isa positive pole and the cathode 604 is a negative pole electrode. It issignificant that the anode 603 is downstream of the cathode and closerto the kidney while the cathode is upstream of the anode and closer tothe spine where the sympathetic nerve traffic is coming from. Theelectric current flowing between the electrodes opposes the normalpropagation of nerve signals and creates a nerve block. Anode 603 andcathode 604 electrodes are connected to the signal generator(stimulator) 306 with wires 606. This embodiment has a practicalapplication even if the device for renal nerve signal modulation isimplanted surgically. During surgery the renal nerve is exposed andcuffs are placed that overlap the nerve. The wires and the stimulatorcan be fully implanted at the time of surgery. Alternatively wires orleads can cross the skin and connect to the signal generator outside ofthe body. An implantable stimulator can be implanted later during aseparate surgery or the use of an external stimulator can be continued.

Clinically used spiral cuffs for connecting to a nerve are manufacturedby Cyberonics Inc. (Houston, Tex.) that also manufactures a fullyimplantable nerve stimulator operating on batteries. See also, e.g.,U.S. Pat. No. 5,251,643. Various external signal generators suitable fornerve stimulation are available from Grass-Telefactor Astro-Med ProductGroup (West Warwick, R.I.). Nerve cuff electrodes are well known. See,e.g., U.S. Pat. No. 6,366,815. The principle of the anodal block isbased on the observation that close to an anodal electrode contact thepropagation of a nerve action potential can be blocked due tohyperpolarization of the fiber membrane. See e.g., U.S. Pat. Nos.5,814,079 and 5,800,464. If the membrane is sufficiently hyperpolarized,action potentials cannot pass the hyperpolarized zone and areannihilated.

As large diameter fibers need a smaller stimulus for their blocking thando small diameter fibers, a selective blockade of the large fibers ispossible. See e.g., U.S. Pat. No. 5,755,750. The activity in differentfibers of a nerve in an animal can be selectively blocked by applyingdirect electric current between an anode and a cathode attached to thenerve.

Antidromic pulse generating wave form for collision blocking is analternative means of inducing a temporary electric blockade of signalstraveling along nerve fibers. See e.g., U.S. Pat. No. 4,608,985. Ingeneral, nerve traffic manipulation techniques such as anodal blocking,cathodal blocking and collision blocking are sufficiently well describedin scientific literature and are available to an expert in neurology.Most of blocking methods allow sufficient selectivity and reversibilityso that the nerve will not be damaged in the process of blocking andthat selective and gradual modulation or suppression of traffic indifferent functional fibers can be achieved.

A nerve is composed of the axons of a large number of individual nervefibers. A large nerve, such as a renal nerve, may contain thousands ofindividual nerve fibers, both myelinated and non-myelinated. Practicalimplementation of physiological blockade of selective nerve fibers in aliving organism is illustrated by the paper “Respiratory responses toselective blockade of carotid sinus baroreceptors in the dog” by FrancisHopp. Both anodal block and local anesthesia by injection of bupivacaine(a common long-acting local anaesthetic, used for surgical anaesthesiaand acute pain management) were applied to the surgically isolated andexposed but intact nerve leading from baroreceptors (physiologicpressure sensors) in the carotid sinus of the heart to the brain of ananimal. Anodal block was induced using simple wire electrodes.Experiments showed that by increasing anodal blocking current from 50 to350 microamperes signal conduction in C type fibers was graduallyreduced from 100% to 0% (complete block) in linear proportion to thestrength of the electric current. Similarly increasing concentration ofinjected bupivacaine (5, 10, 20 and 100 mg/ml) resulted in gradualblocking of the carotid sinus nerve activity in a dog. These experimentsconfirmed that it is possible to reduce intensity of nerve stimulation(nerve traffic) in an isolated nerve in controllable, reversible andgradual was by the application of electric current or chemical blockade.In the same paper it was described that smaller C type fibers wereblocked by lower electric current and higher concentration ofbupivacaine than larger C type fibers.

Gerald DiBona in “Neural control of the kidney: functionally specificrenal sympathetic nerve fibers” described the structure and role ofindividual nerve fibers controlling the kidney function. Approximately96% of sympathetic renal fibers in the renal nerve are slow conductingunmyelinated C type fibers 0.4 to 2.5 micrometers in diameter. Differentfibers within this range carry different signals and respond todifferent levels of stimulation and inhibition. It is known that lowerstimulation voltage of the renal nerve created untidiuretic effect(reduced urine output) while higher level of stimulation createdvasoconstriction effect. Stimulation threshold is inversely proportionalto the fiber diameter; therefore it is likely that elevated signallevels in larger diameter renal nerve C fibers are responsible for theretention of fluid in heart failure. Relatively smaller diameter Cfibers are responsible for vasoconstriction resulting in the reductionof renal blood flow in heart failure.

FIG. 7 illustrates a simplified cross-section of the renal nerve trunk601. Trunk 601 consists of a number of individual fibers. Thestimulation electrode cuff 603 envelops the nerve trunk. Larger C typefiber 705 exemplifies fibers responsible for diuresis. There are alsoother fibers 702 that can be for example afferent fibers. Traffic alongthese fibers can be blocked by the application of lower blocking voltageor lower dose of anesthetic drug. The resulting effect will be diuresisof the CHF patient (secretion of sodium and water by the kidney) and therelief of fluid overload. Smaller C fiber 704 is responsible for theregulation of renal blood flow.

In clinical practice, it may be desired to modulate or block selectivelyor preferably the larger fibers 705. This can be achieved with lowerlevels of stimulation. The patient can be relieved of access fluidwithout significantly increasing renal blood flow since traffic insmaller C fibers will not be altered. Renal blood flow can amount to asmuch as 20% of cardiac output. In a CHF patient with a weakened heartsignificant increase of renal blood flow can lead to a dangerousdecrease of arterial pressure if the diseased heart fails to pump harderto keep up with an increased demand for oxygenated blood. The nervestimulator or signal generator 306 therefore is capable of at least twolevels of stimulation: first (lower) level to block or partially blocksignals propagating in larger C fibers that control diuresis, and second(higher) level to block signals propagating in smaller C fibers thatcontrol renal vascular resistance and blood flow to the kidney. Thelater method of nerve traffic modulation with higher electric currentlevels is useful in preventing damage to kidneys in acute clinicalsituations where the vasoconstriction can lead to the ischemia of akidney, acute tubular necrosis (ATN), acute renal failure and sometimespermanent kidney damage. This type of clinical scenario is oftenassociated with the acute heart failure when hypotension (low bloodpressure) results from a severe decompensation of a chronic heartfailure patient. Acute renal failure caused by low blood flow to thekidneys is the most costly complication in patients with heart failure.

Similar differentiated response to modulation could be elicited byapplying different frequency of electric pulses (overpacing) to therenal nerve and keeping the applied voltage constant. DiBona noted thatrenal fibers responsible for rennin secretion responded to the lowestfrequency of pulses (0.5 to 1 Hz), fibers responsible for sodiumretention responded to middle range of frequencies (1 to 2 Hz) andfibers responsible for blood flow responded to the highest frequency ofstimulation (2 to 5 Hz). This approach can be used when the renal nerveblock is achieved by overpacing the renal nerve by applying rapid seriesof electric pulses to the electrodes with the intent to fatigue thenerve to the point when it stops conducting stimulation pulses.

One embodiment of the method of treating heart failure comprises thefollowing steps:

A. Introducing one or more electrodes in the close proximity with therenal nerve,

B. Connecting the electrodes to an electric stimulator or generator withconductive leads or wires,

C. Initiating flow of electric current to the electrodes sufficient toblock or reduce signal traffic in the sympathetic efferent renal nervefibers with the intention of increasing diuresis, reducing renalsecretion of renin and vasodilation of the blood vessels in the kidneyto increase renal blood supply.

FIG. 8 shows an alternative embodiment of the invention. In thisembodiment the natural efferent signal traffic 804 entering the renalnerve trunk 601 is completely blocked by the anodal block devicestimulator 306 using a pair of electrodes 604 and 603. The thirdelectrode (or pair of electrodes) 803 is situated downstream of theblock. The electrode is used to stimulate or pace the kidney.Stimulation signal is transmitted from the generator 306 via theadditional lead wire 805 to the electrode 803. The induced signalbecomes the nerve input to the kidney. This way full control of nerveinput is accomplished while the natural sympathetic tone is totallyabolished.

FIG. 9 shows the transvenous embodiment of the invention using anodalblockade to modulate renal nerve traffic. Renal nerve 601 is locatedbetween the renal artery 901 and the renal vein 902. It follows the samedirection towards the kidney. Renal artery can branch before enteringthe kidney but in the majority of humans there is only one renal artery.Stimulation catheter or lead 903 is introduced into the renal vein 902and anchored to the wall of the vein using a securing device 904. Thesecuring device can be a barb or a screw if the permanent placement ofthe lead 903 is desired. Electric field 904 is induced by the electriccurrent applied by the positively charged anode 905 and cathode 906catheter electrodes. Electrodes are connected to the stimulator (norshown) by wires 907 and 908 that can be incorporated into the trunk ofthe lead 903. Electric field 904 is induced in the tissue surroundingthe renal vein 902 and created the desired local polarization of thesegment of the renal nerve trunk 601 situated in the close proximity ofthe catheter electrodes 905 and 907. Similarly catheters or leads can bedesigned that induce a cathodal block, a collision block or fatigue thenerve by rapidly pacing it using an induced field rather than bycontacting the nerve directly.

FIG. 10 shows an embodiment where the stimulation lead is placed usinglaparoscopic surgery. This technology is common in modern surgery anduses a small video-camera and a few customized instruments to performsurgery with minimal tissue injury. The camera and instruments areinserted into the abdomen through small skin cuts allowing the surgeonto explore the whole cavity without the need of making large standardopenings dividing skin and muscle.

After the cut is made in the umbilical area a special needle is insertedto start insufflation. A pressure regulated CO2 insufflator is connectedto the needle. After satisfactory insuflation the needle is removed anda trocar is inserted through the previous small wound. This methodreduces the recovery time due to its minimal tissue damage permittingthe patient to return to normal activity in a shorter period of time.Although this type of procedure is known since the beginning of the19th. century, it was not until the advent of high resolution videocamera that laparoscopic surgery became very popular among surgeons.Kidney surgery including removal of donor kidneys is routinely doneusing laparoscopic methodology. It should be easy for a skilled surgeonto place the lead 903 through a tunnel in tissue layers 1001 surroundingthe renal nerve 601. This way lead electrodes 905 and 906 are placed inclose proximity to the nerve and can be used to induce a block withoutmajor surgery.

FIG. 11 shows an implanted embodiment of the invention controlled by thepatient from outside of the body. The implanted stimulation device 203is an electric stimulation device to modulate the renal nerve signal butcan be an implantable infusion pump capable of infusing a dose of ananesthetic drug on command. The implantable device 203 incorporates amagnetically activated switch such as a reed relay. The reed switch canbe a single-pole, single-throw (SPST) type having normally open contactsand containing two reeds that can be magnetically actuated by anelectromagnet, permanent magnet or combination of both. Such switch ofextremely small size and low power requirements suitable for animplanted device is available from Coto Technology of Providence, R.I.in several configurations. Switch is normally open preventing electricor chemical blockade of the renal nerve 209. When the patient brings amagnet 1101 in close proximity to the body site where the device 202 isimplanted the magnetic field 1103 acts on the magnetic switch 1102.Switch is closed and blocking of the renal nerve is activated. Theresulting reduction of the sympathetic tone commands the kidney 208 toincrease the production of urine. Patient can use the device when theyfeel the symptoms of fluid overload to remove access fluid from thebody. The device 202 can be equipped with a timing circuit that is setby the external magnet. After the activation by the magnet the devicecan stay active (block renal nerve activity) for a predeterminedduration of time to allow the kidney to make a desired amount of urinesuch as for an hour or several hours. Then the device will time out toavoid excessive fluid removal or adaptation of the renal nerve to thenew condition.

FIG. 12 illustrates the progression of CRF to ESRD. Following theoriginal injury to the kidney 1201 some nephrons 1202 are lost. Loss ofnephrons lead to hyperfiltration 1203 and triggers compensatorymechanisms 1204 that are initially beneficial but over time make injuryworse until the ESRD 1208 occurs. Compensatory mechanisms lead toelevated afferent and efferent sympathetic nerve signal level (increasedsignal traffic) 1207 to and from the kidney. It is the objective of thisinvention to block, reduce, modulate or otherwise decrease this level ofstimulation.

The effect of the invented therapeutic intervention will be thereduction of central (coming from the brain) sympathetic stimulation1206 to all organs and particularly blood vessels that causesvasoconstriction and elevation of blood pressure. Following thathypertension 1205 will be reduced therefore reducing continuousadditional insult to the kidney and other organs.

FIG. 13 illustrates the physiologic mechanisms of CRF and hypertension.Injured kidney 1302 sends elevated afferent nerve 1306 signals to thebrain 1301. Brain in response increases sympathetic efferent signals tothe kidney 1307 and to blood vessels 1311 that increase vascularresistance 1303 by vasoconstriction. Vasoconstriction 1303 causeshypertension 1304. Kidney 1302 secretes renin 1310 that stimulatesproduction of the vasoconstrictor hormone Angiotensin II 1305 thatincreases vasoconstriction of blood vessels 1303 and further increaseshypertension 1304. Hypertension causes further mechanical damage 1312 tothe kidney 1302 while sympathetically activated neurohormones 1307 andangiotensin II causes more subtle injury via the hormonal pathway 1310.

Invented therapy reduces or eliminates critical pathways of theprogressive disease by blocking afferent 1306 and efferent 1307 signalsto and from the kidney 1302. Both neurological 1311 and hormonal 1309stimulus of vasoconstriction are therefore reduced resulting in therelief of hypertension 1304. As a result, over time the progression ofrenal disease is slowed down, kidney function is improved and thepossibility of stroke from high blood pressure is reduced.

FIG. 14 shows a patient 201 suffering from CRF or renal hypertensiontreated in accordance with the invention. An implantable device 202 isimplanted in the patient's body. An implantable device can be anelectric nerve stimulator or a chemical substance (drug) infusiondevice. The implantable device 202 described above is equipped with thelead 204 connecting it to the renal nerve artery cuff 1401. Cuff 1401envelopes the renal artery 203 that anatomically serves as a supportstructure for the renal nerve plexus. It is understood that there existmany varieties of electrode configurations such as wires, rings,needles, anchors, screws, cuffs and hooks that could all potentially beused to stimulate renal nerves. The cuff configuration 1401 illustratedby FIGS. 14, 15, 16 and 17 was selected for the preferred embodimentbase on the information available to the inventors at the time ofinvention.

The lead conduit can be alternatively an electric wire or a catheter fordelivery of medication or a combination of both. Renal nerve conductsefferent sympathetic stimulation from the sympathetic trunk 206 to thekidney 208. Sympathetic trunk is connected to the patient's spinal cordinside the spine 207. The lead to nerve connection can be locatedanywhere between the kidney 208 and the posterior renal or other renalganglia (not shown) in the region of the 10.sup.th, 11.sup.th and12.sup.th thoracic and 1.sup.st lumbar segments of the spine 207. Thestimulation lead 204 and the arterial nerve cuff 1401, as selected forthe preferred embodiment of the invention, can be placed usinglaparoscopic surgery.

FIG. 15 illustrates one possible embodiment of the renal nervestimulation cuff electrode cuff. When the treated disease is CRF orhypertension it is the additional objective of this embodiment of theinvention to selectively modulate nerve traffic in both afferent andefferent nerve fibers innervating the human kidney. Using existingselective modulation techniques it is possible to stimulate onlyafferent or efferent fibers. Different types of fibers have differentstructure and respond to different levels and frequency of stimulation.Anatomically renal nerve is difficult to locate in humans even duringsurgery. The autonomic nervous system forms a plexus on the externalsurface renal artery. Fibers contributing to the plexus arise from theceliac ganglion, the lowest splanchnic nerve, the aorticorenal ganglionand aortic plexus. The plexus is distributed with branches of the renalartery to vessels of the kidney, the glomeruli and tubules. The nervesfrom these sources, fifteen or twenty in number, have a few gangliadeveloped upon them. They accompany the branches of the renal arteryinto the kidney; some filaments are distributed to the spermatic plexusand, on the right side, to the inferior vena cava. This makes isolatinga renal nerve difficult.

To overcome this anatomic limitation the preferred embodiment of theneurostimulation shown on FIG. 15 has an innovative stimulation cuff.The cuff 1401 envelopes the renal artery 203 and overlaps nerve fibers1501 that form the renal plexus and look like a spider web. Cuff has atleast two isolated electrodes 1402 and 1403 needed for nerve blocking.More electrodes can be used for selective patterns of stimulation andblocking. Electrodes are connected to the lead 204. Renal artery 203connects aorta 213 to the kidney 208. It is subject to pulsations ofpressure and therefore cyclically swells and contracts.

FIG. 16 further illustrates the design of the cuff 1401. Cuff envelopesthe renal artery 203. Cuff is almost circumferential but has an opening406. When the artery cyclically swells with blood pressure pulses, thecuff opens up without damaging the nerve or pinching the artery. Opening406 also allows placement of the cuff around the artery. Similar designsof nerve cuffs known as “helical” cuffs are well known, see e.g., U.S.Pat. Nos. 5,251,634; 4,649,936 and 5,634,462.

FIG. 17 shows the crossection of the cuff 1401. Cuff 1401 is made out ofdielectric material. Two electrodes 1402 and 1403 form rings to maximizethe contact area with the wall of the artery 203.

Common to all the embodiments, is that an invasive device is used todecrease the level of renal nerve signals that are received by thekidney or generated by the kidney and received by the brain. Theinvention has been described in connection with the best mode now knownto the applicant inventors. The invention is not to be limited to thedisclosed embodiment. Rather, the invention covers all of variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

Heart failure, also called congestive heart failure (CHF) and chronicheart failure is a progressive heart disease characterized by lowcardiac output, deterioration of heart muscle and fluid retention. Renalfailure, also called chronic renal failure (CRF) is a progressivedegenerative renal disease that is characterized by gradual loss ofrenal function that leads to the end stage renal disease (ESRD). ESRDrequires dialysis for life. Hypertension is the chronic diseaseassociated with high probability of stroke, renal failure and heartfailure that is characterized by the abnormally high blood pressure.

A nerve in the context of this application means a separate nerve or anerve bundle, nerve fiber, nerve plexus or nerve ganglion. Renal nerveis a part of the autonomic nervous system that forms a plexus on theexternal surface renal artery. Fibers contributing to the plexus arisefrom the celiac ganglion, the lowest splanchnic nerve, the aorticorenalganglion and aortic plexus. The plexus is distributed with branches ofthe renal artery to blood vessels of the kidney, the glomeruli andtubules. The nerves from these sources, have a few ganglia developedupon them. They accompany the branches of the renal artery into thekidney; some filaments are distributed to the spermatic plexus and, onthe right side, to the inferior vena cava.

Nerve stimulation, neurostimulation, nerve modulation andneuromodulation are equivalent and mean altering (reducing orincreasing) naturally occurring level of electric signals propagatingthrough the nerve. The electric signal in the nerve is also called nervetraffic, nerve tone or nerve stimulus.

Nerve block, blocking or blockade is a form of neuromodulation and meansthe reduction or total termination of the propagation or conduction ofthe electric signal along the selected nerve. Nerve block can bepharmacological (induced by a drug or other chemical substance) or anelectric block by electrostimulation. Electric nerve block can be ahyperpolarization block, cathodal, anodal or collision block. Overpacinga nerve can also induce a block. Overpacing means stimulating the nervewith rapid electric pulses at a rate that exceeds the natural cyclingrate of the nerve polarization and depolarization. As a result ofoverpacing the nerve gets fatigued, reserves of the immediatelyavailable neurotransmitter substance in the nerve become exhausted, andthe nerve becomes temporarily unable to conduct signals. Nerve block bythe means listed above can result in the reduction of the nerve signal,in particular the renal sympathetic efferent or afferent tone thatdetermines the electric stimulus received or generated by the kidney.The technique of the controlled reduction of the nerve signal ortraffic, which results in less organ stimulation, is called nerve signalmodulation. Nerve modulation means that the individual nerve fibers firewith a reduced frequency or that fewer of the nerve fibers comprisingthe renal nerve are actively conducting or firing. The increase of nervetraffic or nerve activity usually involves recruitment of larger numberof fibers in the nerve; alternatively less stimulation is associatedwith less active fibers. Denervation means blocking of the renal nerveconduction or the destruction of the renal nerve.

Lead is a medical device used to access the nerve designated forstimulation or blocking. It is usually a tubular device that iselectrically insulated and includes multiple conductors or wires. Wiresconduct stimulation or blocking signals from the stimulator to thedesignated nerve. Wires are terminated in electrodes. Electrodes areconductive terminals and can contact the nerve directly or contact theconductive tissue in the vicinity of the nerve. Electrodes can havedifferent geometric configurations and can be made of differentmaterials. The lead can include lumens or tubes for drug delivery to thenerve. A stimulator or an electrostimulator is an electric device usedto generate electric signals that are conducted by the lead to thenerve. The stimulator can be implanted in the body or external. Electricsignals can be a DC current, voltage, series of pulses or AC current orvoltage. Electrodes can induce an electric field that affects the nerveand results in nerve blocking. Nerve cuff is a support structure that atleast partially envelops the targeted nerve.

While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that the invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

1-20. (canceled)
 21. A method for reducing blood pressure in a humanpatient, the method comprising: implanting a neural stimulation devicein the patient below the patient's skin and adjacent to a targetinnervated region of the patient that contributes to renal function; anddelivering generated stimulation signals from the neural stimulationdevice to the target innervated region of the patient, thereby alteringthe naturally occurring electrical signals propagating through theinnervated region, wherein delivering the generated stimulation signalsto the target innervated region of the patient results in atherapeutically beneficial reduction in blood pressure of the patient.22. The method of claim 21 wherein delivering the generated stimulationsignals from the neural stimulation device to the target innervatedregion comprises delivering intermittent stimulation.
 23. The method ofclaim 21 wherein: implanting a neural stimulation device in the patientcomprises implanting a device comprising a power source, microcircuitry,a housing enclosing the power source and microcircuitry, and one or moreexternal electrodes; and delivering generated stimulation signals fromthe neural stimulation device to the target innervated region comprisesdelivering the stimulation signals via the one or more electrodes. 24.The method of claim 23 wherein delivering the stimulation signals viathe one or more electrodes comprises delivering the stimulation signalsin a unipolar fashion.
 25. The method of claim 23 wherein the neuralstimulation device comprises two electrodes, and wherein delivering thestimulation signals via the two electrodes comprises delivering thestimulation signals in a bipolar fashion.
 26. The method of claim 21wherein the delivered stimulation signal is selected from at least twodifferent levels of stimulation.
 27. The method of claim 21 whereinaltering the naturally occurring electrical signals comprisesattenuating the electrical signals through the innervated region. 28.The method of claim 21 wherein implanting a neural stimulation device inthe patient below the patient's skin and adjacent to a target innervatedregion of the patient comprises implanting the neural stimulation deviceat least proximate renal nerves of the patient.
 29. The method of claim21 wherein delivering generated stimulation signals from the neuralstimulation device to the target innervated region of the patientcomprises decreasing renal sympathetic nerve activity of the patient.30. The method of claim 21, further comprising monitoring at least onecondition of the patient with a sensor.
 31. The method of claim 30,further comprising transmitting information regarding a monitoredphysiologic parameter from the sensor to a device located outside of thepatient.
 32. The method of claim 31 wherein the monitored physiologicparameter comprises at least one of blood pressure and blood oxygensaturation.
 33. The method of claim 31 wherein the monitored physiologicparameter is indicative of renal activity.
 34. The method of claim 21wherein implanting a neural stimulation device in the patient below thepatient's skin and adjacent to a target innervated region of the patientcomprising positioning the neural stimulation device adjacent to renalnerves of the patient.
 35. The method of claim 21 wherein the neuralstimulation device further comprises a lead, and wherein implanting theneural stimulation device in the patient comprises implanting the devicesuch that the lead is attached to or at least proximate renal nerves ofthe patient.